Single lung transplantation in rats with fatal pulmonary hypertension.

Effects of single lung transplantation on fatal pulmonary hypertension were evaluated in rats receiving a lethal dose of monocrotaline. Inbred rats treated with monocrotaline (80 mg/kg) received a left lung isograft at 4 weeks (n = 9) and at 6 weeks (n = 6), when moderate and severe pulmonary hypertension, respectively, had developed. Medicated (n = 12) and nonmedicated rats (n = 12) served as control animals. Each rat was tested weekly with treadmill for exercise tolerance and oxygen consumption during a 10-week period after medication and after they were killed. Medicated control rats lost exercise tolerance and highest oxygen consumption per unit time consistently to the range of resting value (or 45% of nonmedicated control rats), and all died from severe pulmonary vascular occlusive disease with right ventricular hypertrophy before 10 weeks (right ventricular/left ventricular weight ratio of 1.16). All rats receiving a left lung isograft at 4 weeks survived and regained highest oxygen consumption per unit time (87% of nonmedicated control rats), with the lung transplant receiving 65% (nonmedicated control rats, 39%) of cardiac output and milder right ventricular hypertrophy (right ventricular/left ventricular weight ratio of 0.46). Except for one, all rats that received a left lung isograft at 6 weeks tolerated single lung transplantation, but they died soon after reperfusion because of pulmonary edema in the graft that received 58% of cardiac output with right ventricular/left ventricular weight ratio of 0.79. Results of single lung transplantation in rats were dependent on severity of pulmonary hypertension. In rats with moderate pulmonary hypertension, single lung transplantation was successful in reversing exercise intolerance and right ventricular hypertrophy. Single lung transplantation was unsuccessful when pulmonary hypertension was severe in the rat model because increased flow toward the lung transplant resulted in graft pulmonary edema.     

Inhaled carbon monoxide abrogates pulmonary hypertension

Background: Pulmonary hypertension poses a significant clinical challenge. Our current therapies are limited and not efficacious. Carbon monoxide (CO), which is produced endogenously by heme oxygenases, has been shown to possess vasoregulatory properties. Therefore, we hypothesized that inhaled low dose CO would prevent and reverse pulmonary vascular hyperplasia and right ventricular hypertrophy (RVH) in an animal model of pulmonary hypertension. Methods: Monocrotaline (MCT)-treated rats were divided into 4 groups (n = 3-6 per group). Group A received MCT (50 mg/kg, s.c.) alone. Group B was treated with 1 hour daily of inhaled CO (250 ppm) days 1-14 after MCT administration. Group C received CO from days 15-28 and Group D received CO from days 29-42. All animals were sacrificed on day number 43 and their hearts and lungs harvested for morphometric and histologic evaluation. Body weight, right and left ventricular masses, and mean pulmonary arterial pressure (mPAP) were evaluated. Results: MCT caused progressive pulmonary hypertension. By day 42, MCT-treated rats had a mPAP of 35 ± 3.3 compared to untreated controls whose mPAP was 16 ± 2.1 and CO-treated rats which had a mPAP of 20 ± 7.1 (p < 0.05, ANOVA). CO prevented RVH in all treatment groups, even when normalized for body weight (Table) (p < 0.05, Fisher’s Least Significant Difference). Rats treated with MCT alone displayed significant muscularization of the ventricular wall and pulmonary neointimal hyperplasia; CO therapy abrogated these effects. Conclusion: Our data show that low dose inhaled CO decreases mPAP, and prevents RVH and vascular changes in MCT-induced pulmonary hypertension. CO therapy was effective even after the development of cardiac and pulmonary disease. CO may be a useful adjunct in the treatment or prevention of pulmonary hypertension.     

Cardiovascular risk estimates and risk factors in renal transplant recipients

Cardiovascular morbidity, including coronary artery disease and left ventricular hypertrophy, and mortality are high in patients following renal transplantation. Cardiovascular disease is thought to be due to traditional (hypertension, hyperlipidemia, diabetes mellitus and smoking) as well as nontraditional cardiovascular risk factors (microinflammation). Furthermore, immunosuppressive drugs, namely, calcineurin inhibitors, sirolimus, and steroids, have been reported to adversely affect cardiovascular risk factors (e.g., hypertension, hyperlipidemia, hyperglycemia). Evidence from comparative trials and from conversion studies suggest that blood pressure, hyperlipidemia, and hyperglycemia after renal transplantation may be differentially affected by the calcineurin inhibitors cyclosporine and tacrolimus. In the European Tacrolimus versus Cyclosporin A Microemulsion Renal Transplantation Study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) versus cyclosporine (n = 271). In addition, to blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose, we estimated the 10-year risk of coronary heart disease (Framingham risk score). Tacrolimus resulted in a significantly lower time-weighted average of serum cholesterol (P < .001), and mean arterial blood pressure (P < .05), but a higher time-weighted average of blood glucose (P < .01) than cyclosporine. Mean 10-year coronary artery disease risk estimate was significantly lower in men treated with tacrolimus, (10.0% versus 13.2%; P < .01) but was unchanged in women (4.7% versus 7.0%). Tacrolimus and cyclosporine microemulsion have compound-specific effects on cardiovascular risk factors that differentially affect the predicted rate of coronary artery disease.     

A pulmonary hypertension-producing plant from Tanzania.

An African youth who had died from primary pulmonary hypertension was suspected of having ingested a herbal remedy containing the seeds of the local plant Crotalaria laburnoides. Consequently powdered seeds of this plant were fed to 20 Wistar albino rats for 60 dyas to see if this would induce ventricular hypertrophy and associated hypertensive pulmonary vascular disease. At the end of the experimental period right ventricular hypertrophy, medial hypertrophy of the pulmonary trunk and 'muscular pulmonary arteries', and muscularization of the pulmonary arterioles had developed in a proportion of the test animals. These are the morbid anatomical features pathognomonic of a raised pulmonary arterial pressure and show that the seeds of Crotalaria laburnoides contain an agent capable of inducing pulmonary hypertension in rats. This study suggests the value of seeking a history of ingestion of herbal remedies and drugs in cases of unexplained pulmonary hypertension in man.     

Surgically induced unilateral pulmonary hypertension: time-related analysis of a new experimental model.

OBJECTIVE: Patients with irreversible pulmonary vascular obstructive disease caused by pulmonary hypertension due to congenital heart defects are considered either inoperable or only candidates to lung transplantation. This study evaluated an experimental model of surgically induced unilateral pulmonary hypertension. METHODS: In eight pigs, 2-months-old, the left pulmonary artery was divided at the origin and end-to-side anastomosed to the descending thoracic aorta through a left thoracotomy. In this way, increased pulmonary blood flow in the right lung and systemic perfusion pressure and oxygenation in the left lung were obtained. After an interval of 6-12 weeks the animals underwent cardiac catheterization and were then sacrificed. Histological examination was done on both the lungs. RESULTS: The mean left-to-right shunt through the left pulmonary artery diminished from 58.9+/-9.6% at the end of the procedure to 4.5+/-1.5% at the latest hemodynamic evaluation (P<0.01). Pressures and saturations remained identical in aorta and left pulmonary artery, without reduction (NS) with FiO(2)=1.0 ventilation; in the right pulmonary artery there was a mild elevation of the pressures, but still responsive (P<0.05) to FiO(2)=1.0 ventilation. Lung histology showed normal right pulmonary arteries, but irreversible vascular lesions like intimal fibrosis, medial hypertrophy, vascular occlusions, plexiform and dilatation lesions in all the left lungs. CONCLUSIONS: The lung exposed to systemic pressure and oxygenation develops irreversible vascular lesions typical of pulmonary vascular obstructive disease. The lung exposed to increased flow shows only mild elevation of the arterial pressure, remains responsive to oxygen vasodilatation, and displays normal histology.     

Ten years experience with lung and heart-lung transplantation in primary and secondary pulmonary hypertension.

OBJECTIVE: Patients with primary pulmonary hypertension (PPHT) have a worse natural outcome compared with those with secondary pulmonary hypertension in Eisenmenger's syndrome (ES) and chronic pulmonary embolism (CPE). Lung transplantation (SLTx, DLTx, HLTx) still remains the only therapeutical option for patients with this type of endstage lung disease. METHODS: From 1988 to 1998, 63 patients underwent lung transplantation for PPHT (n=29, 9 m, 20 f, 2 SLTx, 14 DLTx, 13 HLTx), ES (n=29, 13 m, 16 f, 2 SLTx, 3 DLTx, 24 HLTx) or CPE (n=5, 2 m, 3 f, 1 SLTx, 2 DLTx, 2 HLTx). Groups were comparable for NYHA functional class, preoperative pulmonary arterial pressure, recipient and donor age, ischemic time, necessity and duration of cardiopulmonary bypass and cross-match. RESULTS: The 1-, 3- and 5-year survival was 52, 40 and 35% for the PPHT-group, 83, 78 and 74% for the ES-group and 80, 60 and 60% for the CPE-group, respectively (P=0.026, P=0.033, P=0.082 for 1-, 3- and 5-year survival). Patients following DLTx showed a lower 1-year survival rate as compared with patients after HLTx both in PPHT patients (36 vs. 62%, P=0.091) and in ES patients (67 vs. 83%, P=0.213). The incidence of bronchiolitis obliterans syndrome was 29% at 1 year and 45% at 3 years for the PPHT-group vs. 17 and 65% for the ES-group (n. s. in between groups). Excluding postoperative ventilation time (PPHT-group: 26.8+/-24.0 days vs. ES-group: 16.1+/-30.8 days, P=0. 011) and a higher incidence of infectious causes of death (PPHT-group n=8 vs. ES-group n=1, P=0.017) groups were comparable with regard to their postoperative courses. CONCLUSIONS: It is concluded, that predominantly the underlying primary disease influences graft survival after lung transplantation in patients with pulmonary hypertension compared with all other patient and procedure dependent factors. Lung transplantation in patients with PPHT requires further investigations to achieve results comparable with other indications.     

Inhaled iloprost in eight heart transplant recipients presenting with post-bypass acute right ventricular dysfunction

BACKGROUND: During heart transplantation, weaning from cardiopulmonary bypass may be particularly laborious as a result of superimposed acute right ventricular dysfunction in the setting of pre-existing pulmonary hypertension. Research in recent years has focused on inhaled vasodilatory treatment modalities which selectively target the pulmonary circulation. METHODS: We present a series of eight patients in whom inhaled iloprost, a synthetic prostacyclin analog, was used to treat pulmonary hypertension and right ventricular dysfunction detected by transesophageal echocardiography during a heart transplant procedure. In addition to conventional inotropic support, 20 mug of inhaled iloprost was administered via nebulized aerosol for a 20-min period. Complete sets of hemodynamic measurements were obtained before inhalation and during and after cessation of the inhalation period. RESULTS: Inhaled iloprost decreased the transpulmonary gradient at the end of the inhalation period relative to baseline (8.2 +/- 1.6 mmHg vs. 11.2 +/- 0.9 mmHg, P < 0.05). The mean pulmonary artery pressure to systemic artery pressure ratio decreased over this period (0.24 +/- 0.07 vs. 0.44 +/- 0.09, P < 0.05). A statistically significant decrease in the pulmonary vascular resistance to systemic vascular resistance ratio was also observed (0.10 +/- 0.02 vs. 0.19 +/- 0.02, P < 0.05). Improved indices of right ventricular function were observed in echocardiographic monitoring. CONCLUSION: During heart transplantation procedures, episodes of pulmonary hypertension can be successfully treated with inhaled iloprost administration, without untoward side-effects or significant systemic impact.     

术前肺动脉高压对肺纤维化患者肺移植术后早期存活率的影响

目的 探讨术前肺动脉高压对特发性肺纤维化(IPE)患者肺移植术后早期(<90 d)存活率的影响.方法 2002年9月至2009年4月为30例特发性肺纤维化患者进行了肺移植.根据术前肺动脉压的检测结果,将30例患者分为两组.肺动脉高压组:13例,术前平均肺动脉压≥30 mmHg;对照组:17例,术前平均肺动脉压<30 mm Hg.对两组患者的年龄、术式(单、双肺移植)、肺动脉乐力、是否应用体外膜氧合(ECMO)等进行多因素逻辑同归分析比较.结果 肺动脉高压组和对照组患者肺移植术后早期存活率分别为61.5%和94.1%,两组比较,差异有统计学意义(P相似文献   

Right ventricle-sparing heart transplantation effective against iatrogenic pulmonary hypertension.

BACKGROUND: Right heart failure is the predominant cause of death following heart transplantation, occurring with disturbingly high frequency in patients with severe antecedent pulmonary hypertension. We have recently reported a novel technique of heart transplantation that spares the recipient right ventricle, excising only the recipient left ventricle. The resulting model has 2 right hearts and 1 left heart. The aim is to preserve the recipient's right ventricle, which is already conditioned to pulmonary hypertension. The hope is that, in this way, death due to right heart failure can be prevented in humans. Our prior report was a feasibility study in normal dogs. This study challenges this new technique by creating iatrogenic pulmonary hypertension in the recipient animals. METHODS: Iatrogenic pulmonary hypertension was created in 4 recipient canines by intravenous injection of the pulmonary toxin monocrotaline pyrrole (single bolus of 3.5 to 4.5 mg/kg intravenously [i.v.]). RESULTS: Within 6 weeks of monocrotaline administration, relative pulmonary hypertension occurred (mean pulmonary artery [PA] pressure 20 mm Hg vs 10 mm Hg for controls [p < 0.01]) (pulmonary vascular resistance [PVR] 4.2 vs 1.5 Wood units [P < 0.01]), and right ventricular (RV) hypertrophy developed (RV thickness 11 mm vs 2 mm [P < 0.04]). Histologic examination confirmed severe muscle infiltration and thickening of the media of the pulmonary arterioles. RV-sparing heart transplantation was performed successfully in all 4 animals with pulmonary hypertension. In all cases, the animals were weaned without difficulty from cardiopulmonary bypass, despite the ambient pulmonary hypertension, on low-dose epinephrine, maintaining systolic blood pressure of 104 mm Hg at right atrial pressure of 7 mm Hg. Both right hearts contracted well without dilation or strain. A single "control" traditional orthotopic transplant experiment in an animal with monocrotaline-induced pulmonary hypertension resulted in immediate death from right heart failure. CONCLUSIONS: Right ventricle-sparing heart transplantation ("one-and-one-half heart model") can handle pulmonary hypertension without difficulty. This evidence adds impetus for further pursuing of right ventricle-sparing heart transplantation to decrease the incidence of death from right heart failure in recipients with severe antecedent pulmonary hypertension.     

Severe pulmonary hypertension in liver transplant candidates

Advanced liver disease with portal hypertension may be associated with pulmonary hypertension. A review of 1,205 consecutive liver transplant patients was made to assess the incidence and severity of pulmonary hypertension in patients with end-stage liver disease. Postoperative data were reviewed to determine if outcome was influenced and, in patients with severe pulmonary hypertension, whether pulmonary hypertension was reversed after transplantation. The hemodynamic data of 5 patients who were found to have severe pulmonary hypertension before transplantation and did not receive transplants were also reviewed. The incidence of pulmonary hypertension in the patients who received transplants was 8.5% (n = 102; mean pulmonary artery pressure, > 25 mmHg). The incidence of mild pulmonary hypertension was 6.72% (n = 81; systolic pulmonary artery pressure, 30 to 44 mmHg); that of moderate pulmonary hypertension was 1.16% (n = 14; systolic pulmonary artery pressure, 45 to 59 mmHg); and that of severe pulmonary hypertension was 0.58% (n = 7; systolic pulmonary artery pressure, > 60 mmHg). Mild and moderate pulmonary hypertension did not influence the outcome of the procedure. Severe pulmonary hypertension was associated with mortality rates of 42% at 9 months posttransplantation and 71% at 36 months posttransplantation. Only 2 of 7 patients with severe pulmonary hypertension have survived liver transplantation with a good quality of life. The remaining 5 patients continued to deteriorate with progressive right heart failure with no evidence of amelioration of the pulmonary hypertension. This experience supports the view that in most patients who have severe pulmonary hypertension associated with advanced liver disease, it is caused by fixed pathological changes in the pulmonary vasculature, is not reversible with liver transplantation, and is associated with a very high perioperative mortality rate. (Liver Transpl Surg 1997 Sep;3(5):494-500)     

二氯乙酸盐对肺动脉高压大鼠肺组织KV1.5表达的影响

目的 探讨二氯乙酸盐对肺动脉高压大鼠肺组织Kv1.5表达的影响.方法 雄性SD大鼠32只,8周龄,体重200～250 g,采用随机数字表法,将大鼠随机分为4组(n=8):正常对照组(C组)、二氯乙酸盐对照组(D组)、肺动脉高压组(PAH组)和二氯乙酸盐治疗组(PD组).采用左肺切除术联合皮下注射野百合碱60mg/kg的方法制备肺动脉高压模型.PD组于皮下注射野百合碱后,给予二氯乙酸盐80mg/kg灌胃,1次/d,连续28 d,PAH组给予等量生理盐水;D组不制备模型,给予相同剂量二氯乙酸盐灌胃.于皮下注射野百合碱后28 d时测定肺动脉压(PAP),随后处死,取肺组织,计算肺小动脉中膜厚度百分比和右心室肥厚指数,采用Western blot法检测增殖细胞核抗原(PCNA)和Kv1.5蛋白的表达水平,采用RT-PCR法检测Kv1.5 mRNA的表达水平.结果 与C组比较,PAH组和PD组PAP、中膜厚度百分比及右心室肥厚指数升高,肺组织Kv1.5 mRNA及其蛋白表达下调,PCNA表达上调(P＜0.05),D组上述指标差异无统计学意义(P＞0.05);与PAH组比较,PD组PAP、中膜厚度百分比及右心室肥厚指数降低,肺组织Kv1.5mRNA及其蛋白表达上调,PCNA表达下调(P＜0.05).结论 二氯乙酸盐减轻大鼠肺动脉高压与上调肺组织Kv1.5表达,抑制肺血管重构有关.

Abstract：

Objective To investigate the effect of dichloroacetate on the expression of Kv1.5 in a rat model of pulmonary arterial hypertension (PAH) .Methods Thirty-two male SD rats weighing 200-250 g were randomly divided into 4 groups ( n = 8 each): normal control group (group C), dichloroacetate control group (group D),PAH group, and PAH + dichloroacetate group (group PD). PAH was induced by left lung resection combined with subcutaneous injection of monocrotaline 60 mg/kg in PAH and PD groups. In group PD, dichloroacetate 80 mg/kg was given through a gastric tube into stomach once a day for 28 consecutive days after monocrotaline injection,while the equal volume of normal saline was given instead of dichloroacetate in group PAH. Group D only received dichloroacetate 80 mg/kg through a gastric tube into stomach once a day for 28 consecutive days. Pulmonary arterial pressure (PAP) was measured at day 28 after monocrotaline injection. The rats were then sacrificed and lung tissues were removed to calculate the percentage of thickness of the tunica media of pulmonary artery and right venicular hypertrophy index and to determine the proliferating cell nuclear antigen (PCNA) and Kv1.5 protein expression (by Western blot) and Kv1.5 mRNA expression (by RT-PCR).Results Compared with group C, the PAP,percentage of thickness of the tunica media, right ventricular hypertrophy index were significantly increased, Kv1.5 mRNA and protein expression was down-regulated and PCNA expression was up-regulated in groups PAH and PD ( P ＜ 0.05). Compared with group PAH, the PAP, percentage of thickness of the tunica media, right ventricular hypertrophy index were significantly decreased, Kv1.5 mRNA and protein expression was up-regulated and PCNA expression was down-regulated in group PD (P ＜ 0.05). There was no significant difference in the indexes mentioned above between group C and group D ( P ＞ 0.05). Conclusion Dichloroacetat alleviates PAH through upregulating Kv1.5 expression in lung tissues and inhibiting pulmonary vascular remodeling in rats.     

Angiotensin converting enzyme activity and evolution of pulmonary vascular disease in rats with monocrotaline pulmonary hypertension.

We have investigated the role of angiotensin converting enzyme (ACE) in the development of pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular disease in rats given a single subcutaneous injection of the pyrrolizidine alkaloid monocrotaline. Thirty-six young female Wistar rats were divided into a test group of 27 animals and a control group of nine animals. Each test rat was given a single subcutaneous injection of monocrotaline (60 mg/kg body weight). On the first, third, fifth, seventh, tenth, twelfth, fourteenth, seventeenth, and twenty-second days after the injection of monocrotaline the mean right ventricular systolic blood pressure was measured in one control and three test rats. The animals were then killed and we measured the specific activity of ACE in serum and lung homogenate. We also evaluated muscularisation of pulmonary arterioles, medial hypertrophy of muscular pulmonary arteries, and right ventricular hypertrophy. The sequence of changes was as follows: muscularisation of pulmonary arterioles and medial hypertrophy of muscular pulmonary arteries were apparent seven days after administration of monocrotaline; pulmonary hypertension and reduced lung ACE activity occurred after 10 days; right ventricular hypertrophy was detected after 12 days. Serum ACE activity was unchanged. It is concluded that the reduction in lung ACE activity is a result rather than a cause of the pulmonary hypertension. This reduction in lung ACE activity may be a protective mechanism designed to limit the elevation of the pulmonary arterial pressure.     

Inelastic vascular prosthesis for proximal aorta increases pulsatile arterial load and causes left ventricular hypertrophy in dogs

OBJECTIVES: Elastic property of the proximal aorta plays an important role in reducing pulsatile load to the ventricle. When a stiff vascular prosthesis is used for the proximal aorta, the pulsatile load increases. We designed this study to elucidate whether the increase in pulsatile load caused left ventricular hypertrophy. METHODS: We created an ascending aorta-abdominal aorta bypass in 9 dogs with a noncompliant vascular prosthesis. The aortic arch proximal to the left subclavian artery was occluded to direct blood flow into the bypass. Closed chest studies were performed after a median of 139 days (range 45-588) days. We assessed the pulsatile load of the ventricle by calculating characteristic impedance from pressure and flow velocity in the ascending aorta. The left ventricle was weighed, normalized with body weight, and compared with the control group, which had sham operations (7 dogs). RESULTS: Characteristic impedance of the bypassed dogs was 175% higher than the control (0.146 +/- 0.056 vs 0.053 +/- 0.014 mm Hg. s. mL(-1), P =.009), which resulted in wider pulse pressure (57 +/- 11 vs 25 +/- 11 mm Hg, P <.001). No difference was found in arterial resistance, cardiac output, or systolic blood pressure. Left ventricular weight normalized by body weight was significantly heavier in the bypass group (5.61 +/- 0.75 vs 4.15 +/- 0.62 g/kg, P =.001). CONCLUSION: Since there was no increase in arterial resistance, we conclude that the increase in pulsatile load was the cause of left ventricular hypertrophy. A stiff vascular prosthesis used for the proximal aorta may cause left ventricular hypertrophy.     

Propensity case-matched analysis of off-pump coronary artery bypass grafting in patients with atheromatous aortic disease

OBJECTIVE: Atheromatous aortic disease is a risk factor for excessive mortality and stroke in patients undergoing coronary artery bypass grafting. Outcomes of off-pump coronary artery bypass grafting and coronary artery bypass grafting with cardiopulmonary bypass in patients with severe atheromatous aortic disease were compared by propensity case-match methods. METHODS: Routine intraoperative transesophageal echocardiography identified 985 patients undergoing isolated coronary artery bypass grafting with severe atheromatous disease in the aortic arch or ascending aorta. Off-pump coronary artery bypass grafting was performed in 281 patients (28.5%). Propensity matched-pairs analysis was used to match patients undergoing off-pump coronary artery bypass grafting (n = 245) with patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. RESULTS: Univariate analysis revealed decreased hospital mortality (16/245, 6.5% vs 28/245, 11.4%; P =.058) and stroke prevalence (4/245, 1.6% vs 14/245, 5.7%; P =.03) in off-pump coronary artery bypass grafting compared with coronary artery bypass grafting with cardiopulmonary bypass. Freedom from any postoperative complication was higher in off-pump coronary artery bypass grafting compared with coronary artery bypass grafting with cardiopulmonary bypass (226/245, 92.2% vs 196/245, 80.0%; P <.001). Multivariable analysis of preoperative risk factors showed that increased hospital mortality was associated with coronary artery bypass grafting with cardiopulmonary bypass (odds ratio = 2.7; P =.01), fewer grafts (P =.05), acute myocardial infarction (odds ratio = 11.5; P <.001), chronic obstructive pulmonary disease (odds ratio = 2.4; P =.03), previous cardiac surgery (odds ratio = 10.2, P =.05), and peripheral vascular disease (odds ratio = 2.1; P =.05). Cardiopulmonary bypass was the only independent risk factor for stroke (odds ratio = 3.6, P =.03). At 36 months' follow-up, comparable survival was observed in the off-pump coronary artery bypass grafting and coronary artery bypass grafting with cardiopulmonary bypass groups (74% vs 72%). Multivariable analysis revealed that renal disease (P <.001), advanced age (P <.001), previous myocardial infarction (P =.03), and lower number of grafts (P =.02) were independent risks for late mortality. CONCLUSIONS: Patients with severe atherosclerotic aortic disease who undergo off-pump coronary artery bypass grafting have a significantly lower prevalence of hospital mortality, perioperative stroke, and overall complications than matched patients who underwent coronary artery bypass grafting with cardiopulmonary bypass. Routine intraoperative transesophageal echocardiography identifies severe atheromatous aortic disease and directs the choice of surgical technique.     

Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery banding.

BACKGROUND: Increased right ventricular (RV) afterload results in RV hypertrophy and dysfunction, as well as increased levels of intracellular beta-adrenergic receptor kinase (betaARK1). We hypothesize that gene transfer of a betaARK1 inhibitor (betaARKct) may improve RV performance, morbidity, and mortality early after pulmonary artery (PA) banding. METHODS: Rabbits underwent PA banding 3 days after right coronary artery injection of an adenovirus containing the gene encoding the betaARKct peptide (n = 14), beta-galactosidase (n = 10), or an empty adenovirus (n = 19). After banding, hemodynamic instability and maximal rate of increase in right ventricular pressure (RV dP/dt(max)) were documented. For 7 days after banding, animals were monitored for mortality, activity, and appetite. RESULTS: When compared with controls, animals receiving the betaARKct transgene showed improvement in survival at 7 days (92.8% +/- 7% vs 48.3% +/- 9%, p = 0.01), less lethargy, a trend toward greater RV dP/dt(max) (NS), and increased hemodynamic stability at the time of banding (78% vs 41%, p = 0.03). CONCLUSIONS: Selective RV expression of betaARKct improves survival and morbidity after PA banding. This represents a novel therapeutic modality for clinical situations involving increased RV afterload.     

Use of two recipient lists for adults requiring heart transplantation

OBJECTIVE: An alternate (second) adult recipient list was used to match excluded potential recipients with nonstandard donor hearts that would otherwise be unused. METHODS: The only absolute criterion for entering the alternate recipient list was age: 65 years old before 1998 and 70 years old after that. Group I consisted of alternates who underwent transplantation, and group II consisted of 401 contemporaneous recipients. Hearts were first offered to regularly listed patients. At least one of the following donor risks accounted for allocation to an alternate: coronary artery disease, reused transplanted heart, high-risk behavior, hepatitis seropositivity, decreased left ventricular ejection fraction, high inotropic requirement, left ventricular hypertrophy, age older than 55 years plus another risk, and small donor with no other matches. RESULTS: Of 102 alternates, 82 were listed were because of age. After a median wait of 107 days, 62 alternates underwent transplantation. Median alternate recipient age was 67 years (vs 54 years, P <.001). Median donor age was 45 years (vs 31 years, P <.001). Survival for alternates at 90 days was 82% (vs 91%, P =.04). Significant recipient predictors of early mortality on multivariable analysis (n = 463) were previous cardiac surgery (odds ratio 2.74, 95% confidence interval 1.37-5.48) and renal dysfunction (odds ratio 1.39, 1.10-176). Alternate listing did not independently predict early or late mortality. Late (>90 days) death rates per 1000 person-months were 4.3 and 3.6 for groups I and II (relative risk 1.2, 0.62-2.36). CONCLUSIONS: Use of two adult recipient lists facilitated allocation of unused donor organs. Satisfactory long-term survival supports the use of an alternate recipient list.     

Right ventricular targeted gene transfer of a beta-adrenergic receptor kinase inhibitor improves ventricular performance after pulmonary artery banding

OBJECTIVE: Abrupt increases in right ventricular afterload occur after cardiac transplantation and pulmonary artery banding, which can result in right ventricular hypertrophy and dilatation. Right ventricular dysfunction is also accompanied by beta-adrenergic receptor desensitization. We sought to determine whether selective right ventricular expression of a transgene encoding a beta-adrenergic receptor kinase inhibitor can improve right ventricular remodeling early after pulmonary artery banding. METHODS: Rabbits underwent pulmonary artery banding 3 days after percutaneous right coronary artery injection of empty adenovirus (n = 19), a control adenovirus containing the beta-galactosidase transgene (n = 10), or an adenovirus containing the beta-adrenergic receptor kinase inhibitor transgene (n = 14). Sham-operated animals (n = 7) underwent instrumentation without deployment of the pulmonary artery band. Right ventricular function was assessed in each rabbit before and 7 days after pulmonary artery banding. Right ventricular mass and dimensions (surface area and volume) were obtained, and biochemical analysis was performed to confirm transgene expression and to characterize beta-adrenergic receptor signaling. RESULTS: Right ventricular mass was increased in animals treated with adenovirus containing the beta-adrenergic receptor kinase inhibitor transgene, adenovirus containing the beta-galactosidase transgene, and empty adenovirus after banding when compared with results in sham-operated animals. However, right ventricular volume and surface area, as measures of dilatation, were significantly lower in pulmonary artery banded rabbits pretreated with adenovirus containing the beta-adrenergic receptor kinase inhibitor transgene when compared with those treated with empty adenovirus or adenovirus containing the beta-galactosidase transgene. Right ventricular contractility and defective beta-adrenergic receptor signaling were significantly enhanced in rabbits expressing the beta-adrenergic receptor kinase inhibitor after pulmonary artery banding. CONCLUSIONS: Right ventricular preconditioning with the beta-adrenergic receptor kinase inhibitor transgene can attenuate the early right ventricular dilatation and dysfunction associated with pulmonary artery banding. Thus beta-adrenergic receptor kinase inhibition might represent a novel target for limiting ventricular remodeling after increased right ventricular afterload.     

Bilateral lung transplantation with intra- and postoperatively prolonged ECMO support in patients with pulmonary hypertension.

OBJECTIVE: Lung transplantation for pulmonary hypertension (PH) is usually performed on cardiopulmonary bypass, with the disadvantage of full systemic anticoagulation, uncontrolled allograft reperfusion and aggressive ventilation. These factors can be avoided with intra- and postoperatively prolonged extracorporeal membrane oxygenator (ECMO) support. PATIENTS AND METHODS: Between February 1999 and March 2001, 17 consecutive patients with PH (systolic pulmonary artery pressure >70 mmHg) of different etiologies underwent bilateral lung transplantation (BLTX). There were 11 females and six males in the age range from 7 to 50 years (mean age, 28.4+/-12.9 years). Six patients were preoperatively hospitalized, four in the intensive care unit (ICU), one was on ECMO for 3 weeks pretransplantation, and one was resuscitated and bridged with ECMO for 1 week until transplantation. Femoral venoarterial ECMO support with heparin-coated circuits was set up after induction of anesthesia and discontinued at the end of surgery (n=3) or extended for 12 h median into the postoperative period (n=14). Postoperative ventilation pressure was kept below 25 mmHg. Allograft function at 2 h after discontinuation of ECMO, outcome and adverse events were monitored in all patients. Mean follow up time was 18+/-11.4 months. RESULTS: The perioperative mortality was 5.9% (n=1). Arterial oxygen pressure measured 2 h after weaning from ECMO, and under standard mechanical ventilation with a peak pressure of 25 mmHg and inspired oxygen fraction of 0.4, was 157+/-28 mmHg. The mean pulmonary artery pressures were reduced to 29+/-3,4 from 66+/-15 mmHg before transplantation. Postoperative complications included rethoracotomy due to bleeding (n=4) and temporary left ventricular failure (n=4). Median ICU stay was 12 days. Incidence of rejection within the first 100 days was 0.4 per patient. CONCLUSION: BLTX with intraoperative and postoperatively prolonged ECMO support provides excellent initial organ function due to optimal controlled reperfusion and non-aggressive ventilation. This results in improved outcome even in advanced forms of PH.     

Single lung transplantation in rats with chemically induced pulmonary hypertension.

Physiologic effects of single lung transplantation on pulmonary hypertension were studied in rats with monocrotaline-induced pulmonary hypertension. Inbred rats treated with monocrotaline (40 mg/kg) received a left lung isograft from a normal donor 2 weeks later, when pulmonary hypertension became significant (transplant group; n = 6). These rats and control rats treated with monocrotaline (mediated control group; n = 11) or vehicle alone (normal control group; n = 9) were followed up weekly by metabolic treadmill testing for exercise tolerance and oxygen consumption up to 6 weeks after monocrotaline (4 weeks after transplantation), when all rats underwent hemodynamic and histologic examinations. Whereas maximal oxygen consumption and exercise tolerance consistently deteriorated in the medicated control group of rats, indices in the transplant group stopped deteriorating 2 weeks after lung transplantation and remained at levels similar to those of normal control rats. Severe pulmonary hypertension (68 +/- 19 mm Hg) and right ventricular hypertrophy (right ventricular/left ventricular weight ratio, 0.95 +/- 0.19) were confirmed in medicated control rats in contrast to transplant animals, in which these two indices remained at normal control levels. Whereas left-to-right lung perfusion ratio was constant among rats not receiving transplants (0.69 +/- 0.16), it was significantly elevated (2.27 +/- 0.65; p less than 0.001) in those receiving transplants, suggesting preferential flow through the lung isograft. The results suggest that, in the early phase of pulmonary hypertension, single lung transplantation shifts pulmonary perfusion to the grafted lung, avoiding right ventricular pressure overload and thereby preserving exercise tolerance at a nearly normal level in rats with monocrotaline-induced pulmonary hypertension.     

盐酸戊乙奎醚对野百合碱致大鼠肺动脉高压的抑制作用

目的探讨盐酸戊乙奎醚是否能够减缓野百合碱导致的大鼠肺动脉高压及是否能够预防或缓解肺血管重构。方法 3~4周龄健康雄性SD大鼠30只,体重90~100g,随机均分为正常对照组(C组)、野百合碱肺高压组(M组)、盐酸戊乙奎醚组(P组),每组10只。M组和P组腹腔注射野百合碱60mg/kg建造大鼠肺动脉高压模型,C组腹腔注射等容量生理盐水。P组大鼠于建模前15min时腹腔注射盐酸戊乙奎醚2mg/kg,建模第2天腹腔注射盐酸戊乙奎醚1mg/kg,C组和M组在相应时点腹腔注射等容量生理盐水,连续使用3周。在建模后第21天,三组大鼠检测血流动力学(肺动脉压、右心室压);处死大鼠前采集静脉血以备血液生化检测:ELISA法检测一氧化氮(NO)含量、内皮素-1(ET-1)含量。处死大鼠后留取左肺组织行病理切片以观察肺组织病理形态学变化,取右肺组织于-80℃冻存以备后续检测。结果 M组和P组右心室SBP、平均肺动脉压、肺动脉SBP和肺动脉DBP明显高于C组(P0.05);P组右心室SBP、平均肺动脉压、肺动脉SBP和肺动脉DBP明显低于M组(P0.05)。M组肺小动脉明显增厚,肺小动脉管腔狭窄甚至闭塞,肺组织炎性细胞浸润非常明显。P组肺小动脉壁增厚减轻,肺组织炎性细胞浸润减轻。M组大鼠血清中NO含量明显低于,ET-1的含量明显高于C组(P0.05);P组大鼠血清中NO含量明显高于M组和C组(P0.05),ET-1含量明显高于C组,但明显低于M组(P0.05)。结论使用野百合碱成功建造了大鼠肺动脉高压模型,NO含量降低、ET-1含量增加可能与野百合碱致大鼠肺动脉高压的形成有关;盐酸戊乙奎醚减缓野百合碱致大鼠肺动脉高压模型的肺动脉压力的升高、改善肺小动脉壁增厚可能与增加NO含量、降低ET-1含量有关。